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Cell death & disease
12 20, 2019;10 (12): 959.

TIPRL potentiates survival of lung cancer by inducing autophagy through the eIF2α-ATF4 pathway.

Su-Jin Jeon, Jun-Ho Ahn, Debasish Halder, Hyun-Soo Cho, Jung-Hwa Lim, Soo Young Jun, Jeong-Ju Lee, Ji-Yong Yoon, Min-Hyuk Choi, Cho-Rok Jung, Jin-Man Kim, Nam-Soon Kim
Author Information
  1. Su-Jin Jeon: Genome Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, Republic of Korea.
  2. Jun-Ho Ahn: Genome Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, Republic of Korea.
  3. Debasish Halder: Genome Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, Republic of Korea.
  4. Hyun-Soo Cho: Genome Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, Republic of Korea.
  5. Jung-Hwa Lim: Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon, Republic of Korea.
  6. Soo Young Jun: Genome Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, Republic of Korea.
  7. Jeong-Ju Lee: Genome Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, Republic of Korea.
  8. Ji-Yong Yoon: Genome Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, Republic of Korea.
  9. Min-Hyuk Choi: Genome Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, Republic of Korea.
  10. Cho-Rok Jung: Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon, Republic of Korea.
  11. Jin-Man Kim: Department of Pathology, School of Medicine, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, Republic of Korea.
  12. Nam-Soon Kim: Genome Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, Republic of Korea. nskim37@kribb.re.kr.
PMID: 31862913 DOI: 10.1038/s41419-019-2190-0

Abstract

Autophagy, an intracellular system of degrading damaged organelles and misfolded proteins, is essential for cancer cell survival. Despite the progress made towards understanding the mechanism, identification of novel autophagy regulators presents a major obstacle in developing anticancer therapies. Here, we examine the association between the TOR signaling pathway regulator-like (TIPRL) protein and autophagy in malignant transformation of tumors. We show that TIPRL upregulation in non-small cell lung cancer (NSCLC) potentiated autophagy activity and enabled autophagic clearance of metabolic and cellular stress, conferring a survival advantage to cancer cells. Importantly, the interaction of TIPRL with eukaryotic initiation factor 2α (eIF2α) led to eIF2α phosphorylation and activation of the eIF2α-ATF4 pathway, thereby inducing autophagy. Conversely, TIPRL depletion increased apoptosis by reducing autophagic clearance, which was markedly enhanced in TIPRL-depleted A549 xenografts treated with 2-deoxy-D-glucose. Overall, the study indicated that TIPRL is a potential regulator of autophagy and an important drug target for lung cancer therapy.

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Grants

  1. 2014M3A9A5034157/Ministry of Science, ICT and Future Planning (MSIP)
  2. 2014M3C9A2064619/Ministry of Science, ICT and Future Planning (MSIP)

MeSH Term

A549 Cells
Activating Transcription Factor 4
Animals
Apoptosis
Autophagy
Carcinoma, Non-Small-Cell Lung
Cell Survival
Endoplasmic Reticulum Stress
Eukaryotic Initiation Factor-2
Female
Heterografts
Humans
Intracellular Signaling Peptides and Proteins
Lung Neoplasms
Male
Mice
Phosphorylation
Signal Transduction
Spheroids, Cellular

Chemicals

ATF4 protein, human
EIF2S1 protein, human
Eukaryotic Initiation Factor-2
Intracellular Signaling Peptides and Proteins
TIPRL protein, human
Activating Transcription Factor 4
Journal Article Research Support, Non-U.S. Gov't
Article has an altmetric score of 2

Word Cloud

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